US7074392B1 - Controllled delivery system of antifungal and keratolytic agents for local treatment of fungal infections - Google Patents
Controllled delivery system of antifungal and keratolytic agents for local treatment of fungal infections Download PDFInfo
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- US7074392B1 US7074392B1 US09/534,960 US53496000A US7074392B1 US 7074392 B1 US7074392 B1 US 7074392B1 US 53496000 A US53496000 A US 53496000A US 7074392 B1 US7074392 B1 US 7074392B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q3/00—Manicure or pedicure preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q3/00—Manicure or pedicure preparations
- A61Q3/02—Nail coatings
Definitions
- the present invention relates to a sustained release composition in the form of varnish or spray comprising an antifungal agent, a keratolytic agent, or preferably a combination of antifingal and keratolytic agents, for local treatment of fungal infections of the nails and/or surrounding tissues.
- the composition additionally features a humectant, water, one or more film-forming polymers, and solvents.
- the composition may further comprise an antibacterial agent, an antiviral agent, an antipsoriatic agent or a combination thereof.
- Fungal infections are probably the most common disorder of nails encountered in medical practice. It has been estimated that approximately 90% of elderly people have some degree of toenail involvement with fungi. Conditions of moisture and occlusion of the lower extremities favor fungal colonization. Pain may result from extreme deformity of the nail plate, but usually, the complaint is one of cosmetic appearance.
- the most common organisms involved in the fungal infections of the nail are Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Candida albicans, Microsporum persiccolor , Cephalosporium species, Aspergillus species, and Fusarium oxysporum.
- Fingernail infection is of far greater importance cosmetically and notably clears faster than toenail infection because of the more rapid growth rate of fingernails. Despite this, 4-6 months of oral griseofulvin may be required to bring about complete clearing of the fingernail. For toenail infections with extensive involvement of multiple digits, withholding treatment may be the best decision. One of the factors in the treatment decision is whether the patient is taking other medications, as griseoftilvin interacts with several drugs, including anticoagulants.
- Griseofulvin was the drug of choice for many years, but its low cure rate and the development of newer, more effective drugs has caused it to lose favor.
- Current therapeutic alternatives include itraconazole and terbinafine. These drugs are well tolerated, but attention to drug interactions is still necessary [Trepanier, E. F and Amsden, G. W. Annals of Pharmacotherapy , 32, 1998, 204-214].
- Creams or solutions containing antifungal agents are able to deliver the active agent to the nail only for a short period of time and their permeability/penetration through the nail is very low.
- U.S. Pat. No. 5,120,530 discloses an antimycotically-active nail varnish, containing an antimycotically-active substance (a morpholine derivative) and a water-insoluble film former which is a copolymerizate of acrylic acid esters and methacrylic acid esters having a low content of quaternary ammonium groups.
- the formulations disclosed are expected to be poorly effective because they do not contain a keratolytic agent or a humectant. As a result, the nail permeability and consequently the penetration of the antimycotic agent will be very low.
- the humectant entraps the water in the film after evaporation of the organic solvents, thus enabling the solubilization of the active agents in the film. Because the water content of the nail is very low, the presence of water in the film should hydrate the nail and improve the transport of the active agents into the nail. The keratolytic agent should also help by increasing the penetration of the antifungal agent into the deeper layers of the nail.
- U.S. Pat. No. 4,957,730 discloses a nail varnish comprising a water-insoluble film-forming substance and an antimycotic substance, specifically 1-hydroxy-2-pyridones.
- the formulations disclosed do not contain a humectant.
- the nail permeability of the formulations disclosed and consequently the penetration of the active agent into the deeper layers of the nail is expected to be very low, thereby failing to achieve the desired pharmacological action and cure.
- U.S. Pat. No. 5,814,305 discloses a nail preparation comprising an antifungal agent, at least one hydrophilic penetration agent, and a water-alcohol solvent medium.
- the formulations disclosed are disadvantageous; they are in the form of a lotion or fluid gel and do not contain a film-forming agent. As a result a sustained release action is not achieved with these formulations.
- the formulations disclosed are disadvantageous since such a dosage form would require multiple applications of the formulation, leading to poor patient compliance. Because of the hydrophilic character of the formulations, in the presence of water or mechanical contact, the lotion or gel will likely be washed off or removed from the nail, thereby reducing the accumulation of the active agents in the nail.
- UK Patent Appl. No GB2202743 A discloses a topical antifungal composition in the form of a lotion, gel or varnish, comprising at least 1% by weight (relative to the total weight of the composition) of miconazole nitrate or econazole nitrate dissolved in a mixture of water, urea, and a water-soluble dissolving intermediary.
- Urea is used in the formulation as a solubility increasing agent.
- the composition is in the form of a varnish it contains a resin.
- the lotion and gel formulations disclosed are disadvantageous since such a dosage form will not provide sustained release action and would require multiple applications of the formulation, leading to poor patient compliance.
- U.S. Pat. No. 5,346,692 discloses a nail lacquer for treating onychomycosis, which comprises (a) a film former agent, (b) at least one antimycotically active substance, (c) urea; and (d) a solvent which comprises (i) 50-70 wt. % of acetone; and (ii) 30-50 wt. % of 90 volume % aqueous ethanol.
- the formulations disclosed are disadvantageous since they use high concentrations of the antimycotically active substance and urea, thereby causing unwanted adverse effects (for example irritation and burning) which leads to poor compliance.
- the formulations disclosed do not contain glycerol which would entrap the water in the film after evaporation of the organic solvents.
- the presence of water in the film enables the active agents to be maintained in a soluble form that is readily available for pharmacological action. Since the water content in the nail is very low, the presence of water in the film hydrates the nail so that the active agents can be delivered into deeper layers of the nail.
- This formulation would feature a film-forming agent and a humectant preferably glycerol, for trapping water in the film formed on the nail, and the water so trapped would hydrate the nail for delivery of the agent thereto.
- This formulation would be lower in cost because of the lower concentrations of the antifungal and keratolytic agents. Additionally, such formulation would reduce the unwanted side effects caused by high concentrations of the antifungal and keratolytic agents and yet be suitable for treatment of fungal infections of the nail and surrounding tissues.
- the present invention provides a pharmaceutical sustained release preparation in a varnish or spray form for local treatment of the nail and surrounding tissues, where the active ingredient is an antifungal agent, a keratolytic agent, or preferably a combination of an antifungal and a keratolytic agent.
- the composition may further comprise an antibacterial, an antiviral, an antipsoriatic agent or combinations thereof.
- the pharmaceutically effective agent is selected from the group consisting of an antifungal agent, a keratolytic agent, and mixtures thereof.
- the antifungal agent is selected from the group consisting of amphothericin B, butefanine, butoconazole, carbol-fuchsin, ciclopirox, clioquinol, clotrimazole, econazole, gentian violet, ketoconazole, miconazole, naftifine, nystatin, oxiconazole, sodium thiosulfate, terbinafine, terconazole, tolnaftate, undecylenic acid, therapeutically acceptable salts thereof, derivatives thereof, and mixtures thereof.
- the concentration of the antifungal agent in the varnish solution is less than about 1% (w/w).
- the antifungal agent is present in concentration of less than about 5% (w/w) based on the weight of the non-volatile components.
- the keratolytic agent is selected from the group consisting of urea, sulfur, salicylic acid, podophyllum resin, and mixtures thereof.
- the concentration of the keratolytic agent in the varnish solution is less than about 1% (w/w).
- the keratolytic agent is present in concentration of from about 0.05% to about 5% (w/w), based on the weight of the non-volatile components.
- the pharmaceutically effective agent further comprises an antibacterial, an antiviral, an antipsoriatic agent, or mixtures thereof.
- the antibacterial agent is selected from the group consisting of bacitracin, clindamycin, erythromycin, gentamicin, mupirocin, neomycin, tetracyclines, polymyxin B, benzalkonium chloride, boric acid, hexachlorophene, iodine, iodoquinol, mafenide, mercury ammoniated, metronidazole, nitrofurazone, selenium sulfide, silver sulfadiazine, salts thereof, derivatives thereof, and mixtures thereof.
- the concentration of the antibacterial agent in the varnish solution is from about 0.01% to about 1% (w/w).
- the antibacterial agent is present in concentration of from about 0.05% to about 5% (w/w), based on the weight of the non-volatile components.
- the antiviral agent is selected from the group consisting of acyclovir, amantadine, cidofovir, famciclovir, foscarnet, ganciclovir, palivizumab, penciclovir, ribavirin, rimantadine, valcyclovir, salts thereof, derivatives thereof, and mixtures thereof.
- the concentration of the antiviral agent in the varnish solution is from about 0.08% to about 0.8% (w/w).
- the antiviral agent is present in concentration of from about 0.8% to about 8% (w/w), based on the weight of the non-volatile components.
- the antipsoriatic agent is selected from the group consisting of alclometasone, ameinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, halcinonide, hydrocortisone, mometasone, prednicarbate and triamcinolone, salts thereof, derivatives thereof, and mixtures thereof.
- the concentration of the antipsoriatic agent in the varnish solution is from about 0.02% to about 2% (w/w).
- the antipsoriatic agent is present in concentration of from about 0.1% to about 10% (w/w), based on the weight of the non-volatile components.
- the humectant is selected from the group consisting of glycerol, sorbitol, and mixtures thereof.
- the concentration of the humectant in the varnish solution is from about 3% to about 15% (w/w).
- the humectant is present in concentration of from about 5% to about 35% (w/w), based on the weight of the non-volatile components.
- the water concentration in the varnish solution is less than about 5% (w/w).
- the concentration of the water in the film is from about 0.4% to about 25% (w/w).
- the polymeric film-forming agent is selected from the group consisting of hydrophobic (water insoluble) polymers.
- the hydrophobic (water insoluble) polymer is selected from the group consisting of hydrophobic cellulose derivatives, hydrophobic methacrylic polymers, cellulose acetate phthalate, shellac, derivatives thereof, and mixtures thereof.
- the hydrophobic cellulose derivative is selected from the group consisting of ethyl cellulose of any acceptable molecular weight.
- the hydrophobic methacrylic polymer is selected from the group consisting of methacrylic acid copolymer type B (USP/NF), methacrylic acid copolymer type C (USP/NF), ammonio methacrylate copolymer type B (USP/NF) and ammonio methacrylate copolymer type A (USP/NF), derivatives thereof, and mixtures thereof
- the hydrophobic methacrylic polymer is selected from the group consisting of Eudragit S, Eudragit L, Eudragit RS, and Eudragit RL manufactured by Rohm Pharma, but hydrophobic methacrylic polymers from other sources can also be used.
- the concentration of the polymeric film-forming agent in the varnish solution is less than about 7.5% (w/w).
- the polymeric film-forming agent is present in concentration of from about 8% to about 35% (w/w), based on the weight of the non-volatile components.
- the weight ratio of polymer to the antifungal agent is in the range from about 1:0.01 to about 1:0.3.
- the weight ratio of polymer to the keratolytic agent is in the range from about 1:0.01 to about 1:1.
- the weight ratio of polymer to antibacterial agent is in the range from about 1:0.01 to about 1:0.3.
- the weight ratio of polymer to antiviral agent is in the range from about 1:0.02 to about 1:0.2.
- the weight ratio of polymer to antipsoriatic agent is in the range from about 1:0.006 to about 1:0.15.
- the at least one additional excipient is selected from a group consisting of plasticizers.
- the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate, lanolin alcohols, mineral oil, petrolatum, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, and mixtures thereof.
- the concentration of the plasticizer in the varnish solution is from about 0.1% to about 2% (w/w).
- the plasticizer is present in concentration of from about 0.5% to about 10% (w/w), based on the weight of the non-volatile components.
- the weight ratio of the plasticizer to the polymer is in the range from about 0.04:1 to about 0.3:1.
- the volatile solvent is selected from the group consisting of an alcohol, a ketone, and mixtures thereof.
- the alcohol is selected from the group consisting of ethanol, isopropyl alcohol, methanol and mixtures thereof.
- the ketone is acetone
- the volatile solvent is a mixture of acetone and isopropyl alcohol.
- the volatile solvent is present in an amount of is from about 60% to about 90% (w/w), relative to the total weight of the composition.
- volumetric ratio of acetone to isopropyl alcohol is in the range from about 1:4 to about 4:1.
- the solvent system further includes at least one non-volatile solvent selected from the group consisting of benzyl alcohol, benzyl benzoate, corn oil, cottonseed oil, ethyl oleate, glycerin, glycofural, isopropyl myristate, isopropyl palmitate, mineral oil, peanut oil, polyethylene glycol, propylene glycol, propylene carbonate, sesame oil, soybean oil, water, and mixtures thereof.
- benzyl alcohol benzyl benzoate
- corn oil cottonseed oil
- ethyl oleate glycerin
- glycofural isopropyl myristate
- isopropyl palmitate mineral oil
- peanut oil polyethylene glycol
- propylene glycol propylene carbonate
- sesame oil sesame oil
- soybean oil water, and mixtures thereof.
- composition may further comprise preservatives, antioxidants, surfactants and coloring agents.
- the present invention provides a method of preparing a sustained release varnish or spray formulation for treating the nail and surrounding tissues, comprising the steps of (a) preparing a solution including at least one volatile solvent; (b) adding water to the solution prepared in (a); (c) dissolving the pharmaceutically effective agents, and excipients in the solution prepared in (b); (d) adding the humectant to the solution prepared in (c) when the formulation ingredients are completely Is dissolved; and (e) dissolving the polymeric film-forming agents in the solution prepared in (d).
- film is meant the non-volatile components, which are remained after evaporation of the volatile components of the varnish solution.
- concentration or amount relative to the total weight of the composition is meant concentration in the varnish solution, before application to the nail or before evaporation of the volatile components.
- concentration or amount based on the weight of the non-volatile components is meant concentration based on the weight of the components remaining after evaporation of the volatile components (i.e. concentration in the film).
- the aim of this invention was to develop a sustained release delivery system for antifungal agents achieving high penetration through the nail by combining the antifungal agent with a keratolytic agent and a humectant.
- the present invention provides a topical, sustained release pharmaceutical preparation in a varnish or spray form for treating the nail and surrounding tissues, where the active ingredient is an anti-fungal agent, a keratolytic agent, or preferably a combination of an antifungal and a keratolytic agent.
- the composition may further comprise an antibacterial, an antiviral, an antipsoriatic agent or combinations thereof.
- the composition features an effective quantity of at least one antifungal agent, an effective quantity of at least one keratolytic agent, a humectant, water, polymers, optionally at least one additional pharmaceutical excipient and finally a solvent medium.
- the additional excipients include plasticizers.
- the composition may further comprise an effective quantity of at least one antibacterial, antiviral, antipsoriatic agent or combinations thereof.
- the delivery system is in the form of a solution or spray for self-application by the patient. After application of the solution to the nail surface, the solvent evaporates and a film/coating is formed on the surface.
- the film/coating has the capacity to release the antifungal and keratolytic agents in therapeutic levels over a prolonged period of time.
- the combination of an antifungal and keratolytic agent is advantageous because it increases the penetration of the antifungal agent through the nail. Because the amount of water in the nail is very low, it is essential to achieve relatively high concentrations of water in the film.
- the humectant is added to the present invention in order to retain water in the film after the evaporation of the organic solvents.
- the film formed after evaporation of the volatile solvents contains the pharmaceutically effective agents, polymers, humectant, the water entrapped by the humectant, and additional non-volatile excipients.
- the presence of water in the film is of significant importance because it maintains the active agents in a saturated-reservoir solution, thus enabling the solubilized agents to be released in a controlled manner into the nail.
- the antifungal agents are preferably amphothericin B, butefanine, butoconazole, carbol-fuchsin, ciclopirox, clioquinol, clotrimazole, econazole, gentian violet, ketoconazole, miconazole, naftifine, nystatin, oxiconazole, sodium thiosulfate, terbinafine, terconazole, tolnaftate, undecylenic acid, therapeutically acceptable salts thereof, derivatives thereof, and mixtures thereof, more preferably clotrimazole and miconazole nitrate, most preferably miconazole nitrate.
- concentration of the antifungal agents in the varnish solution is less than about 1% (w/w) and most preferably 0.3-0.9% (w/w).
- the concentration of the antifungal agents based on the weight of the non-volatile components is less than about 5% (w/w) and most preferably 0.3-4.7% (w/w).
- the keratolytic agents are added to the present invention in order to increase the permeability of and penetration into the nail.
- the keratolytic agents are preferably urea, sulfur, salicylic acid, podophyllum resin, and mixtures thereof, most preferably urea.
- concentration of the keratolytic agents in the varnish solution is less than about 1% (w/w), and most preferably 0.3-0.9% (w/w).
- concentration of the keratolytic agent based on the weight of the non-volatile components is in the range from about 0.05% to about 5% (w/w).
- the antibacterial agents are preferably bacitracin, clindamycin, erythromycin, gentamicin, mupirocin, neomycin, tetracyclines, polymyxin B, benzalkonium chloride, boric acid, hexachlorophene, iodine, iodoquinol, mafenide, mercury ammoniated, metronidazole, nitrofurazone, selenium sulfide, silver sulfadiazine, salts thereof, derivatives thereof, and mixtures thereof
- concentration of the antibacterial agents in the varnish solution is in the range from about 0.01% to about 1% (w/w), and most preferably 0.2-0.8% (w/w).
- concentration of the antibacterial agents based on the weight of the non-volatile components is in the range from about 0.05% to about 5% (w/w) and most preferably 1.5-4.5% (w/w).
- the antiviral agents are preferably acyclovir, amantadine, cidofovir, famciclovir, foscarnet, ganciclovir, palivizumab, penciclovir, ribavirin, rimantadine, valcyclovir, salts thereof, derivatives thereof, and mixtures thereof.
- concentration of the antiviral agents in the varnish solution is in the range from about 0.08% to about 0.8% (w/w) and most preferably 0.2-0.6% (w/w).
- concentration of the antiviral agents based on the weight of the non-volatile components is in the range from about 0.8% to about 8% (w/w) and most preferably 2-6% (w/w).
- the antipsoriatic agents are preferably alclometasone, amcinonide, betamethasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, flurandrenolide, halcinonide, hydrocortisone, mometasone, prednicarbate, triamcinolone, salts thereof, derivetives thereof, and mixtures thereof.
- concentration of the antipsoriatic agents in the varnish solution is in the range from about 0.02% to about 2% (w/w) and most preferably 0.2-1.5% (w/w).
- concentration of the antipsoriatic agents based on the weight of the non-volatile components is in the range from about 0.1% to about 10% (w/w) and most preferably 1-7.5% (w/w).
- the humectant is added to the varnish solution in order to hold the water in the film after evaporation of the organic solvents.
- the presence of water in the film hydrates the nail so that the active agents can be delivered into the deeper layers of the nail.
- the humectant is preferably glycerol, sorbitol, and mixtures thereof, most preferably glycerol.
- concentration of the humectant in the varnish solution is in the range from about 3% to about 15% (w/w), and most preferably 4-10% (w/w).
- the concentration of the humectant based on the weight of the non-volatile components is in the range from about 5% to about 35% (w/w), and most preferably 10-30% (w/w).
- glycerol can serve at lower concentrations (less than 2% w/w based on the total weight of the composition) as a plasticizer, at this lower concentration range glycerol is not efficient as a humectant and therefore higher concentrations (above 3% w/w) of glycerol are required in order to be effective as a humectant.
- the water concentration in the varnish solution is less than about 5% (w/w), more preferably 0.5-4.5% (w/w) and most preferably 1-4.5% (w/w).
- concentration of the water in the film is in the range from about 0.4% to about 25% (w/w), more preferably 0.8-20% (w/w), and most preferably 2-18% (w/w).
- the delayed release polymeric film-forming agents are preferably hydrophobic (water insoluble) polymers.
- the hydrophobic (water insoluble) polymers are preferably hydrophobic cellulose derivatives, hydrophobic methacrylic polymers, cellulose acetate phthalate, shellac, derivatives thereof and mixtures thereof.
- the hydrophobic cellulose derivatives are preferably ethyl cellulose of any acceptable molecular weight.
- the hydrophobic methacrylic polymers are preferably methacrylic acid copolymer type B (USP/NF), methacrylic acid copolymer type C (USP/NF), ammonio methacrylate copolymer type B (USP/NF) and ammonio methacrylate copolymer type A (USP/NF), derivatives thereof, and mixtures thereof.
- the hydrophobic methacrylic polymers are preferably Eudragit S, Eudragit L, Eudragit RS, and Eudragit RL manufactured by Rohm Pharma, but hydrophobic methacrylic polymers from other sources can also be used.
- the polymers provide a uniform film, retard the release rate of the drugs (agents), and can be mixed in regulated amounts to attain the desired drug release characteristics.
- the concentration of the polymeric film-forming agent in the varnish solution is less than about 7.5% (w/w).
- concentration of the polymeric film-forming agent based on the total weight of the non-volatile components is in the range from about 8% to about 35% (w/w), more preferably 18-30% (w/w) and most preferably 23-27% (w/w).
- the weight ratio of polymer to the antifungal agent is in the range from about 1:0.01 to about 1:0.3 and most preferably is in the range from about 1:0.06 to about 1:0.25.
- the weight ratio of polymer to the keratolytic agent is in the range from about 1:0.01 to about 1:1 and most preferably is in the range from about 1:0.05 to about 1:1.
- the weight ratio of polymer to antibacterial agent is in the range from about 1:0.01 to about 1:0.3 and most preferably is in the range from about 1:0.05 to about 1:0.25.
- the weight ratio of polymer to antiviral agent is in the range from about 1:0.02 to about 1:0.2 and most preferably is in the range from about 1:0.05 to about 1:0.2.
- the weight ratio of polymer to antipsoriatic agent is in the range from about 1:0.006 to about 1:0.15, and most preferably is in the range from about 1:0.01 to about 1:0.15.
- Plasticizers are added to the varnish solution in order to enhance the plasticity of the film formed and to modify the sustained release characteristics of the polymer.
- the plasticizer is preferably dibutyl sebacate, diethyl phthalate, lanolin alcohols, mineral oil, petrolatum, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, or mixtures thereof, and most preferably polyethylene glycol with molecular weight of 300-6000.
- the concentration of the plasticizer in the varnish solution is in the range from about 0.1% to about 2% (w/w), more preferably 0.2-1% (w/w), and most preferably 0.4-0.8% (w/w).
- concentration of the plasticizer based on the total weight of the non-volatile components is in the range from about 0.5% to about 10% (w/w), more preferably 1-5% (w/w), and most preferably 2-3% (w/w).
- the weight ratio of the plasticizer to the polymer is in the range from about 0.04:1 to about 0.3:1, and most preferably, the weight ratio of the plasticizer to polymer is in the range from about 0.05:1 to about 0.2:1.
- the volatile solvent is selected from the group consisting of an alcohol, a ketone, and mixtures thereof
- the alcohol is preferably ethanol, isopropyl alcohol, methanol and mixtures thereof
- the ketone is preferably acetone.
- the volatile solvent is a mixture of acetone and isopropyl alcohol.
- the volatile solvent is present in an amount of from about 60% to about 90% (w/w), and most preferably from about 70% to about 85% (w/w) relative to the total weight of the composition.
- volumetric ratio of acetone to isopropyl alcohol is in the range from about 1:4 to about 4:1 and most preferably from about 1:3 to about 3:1.
- the solvent system further includes at least one non-volatile solvent.
- the at least one non-volatile solvent is preferably benzyl alcohol, benzyl benzoate, corn oil, cottonseed oil, ethyl oleate, glycerin, glycofural, isopropyl myristate, isopropyl palmitate, mineral oil, peanut oil, polyethylene glycol, propylene glycol, propylene carbonate, sesame oil, soybean oil, water, and mixtures thereof.
- Optional ingredients include at least one additive chosen from among the group consisting of preservatives, antioxidants, surfactants and coloring agents which are well known in the art.
- the preservative is preferably benzoic acid, benzyl alcohol, bronopol, butyl paraben, chlorbutanol, chlorocresol, cresol, ethyl paraben, methyl paraben, phenol, propyl paraben, sodium benzoate, sodium propionate, sorbic acid, or mixtures thereof
- the antioxidant is preferably alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, ftimaric acid, malic acid, propyl gallate, sodium ascorbate, sodium metabisulfite, or mixtures thereof.
- the surfactant is preferably cetrimide, sodium lauryl sulfate, docusate sodium, glyceryl monooleate, polysorbates, sorbitan esters, or mixtures thereof
- the coloring agent is preferably amaranth, brilliant blue, caratenoids, carmoisine, curcumin, eosine, erythrosine, fluorescein, rhodoxantin, tetrazine, or mixtures thereof.
- composition prepared according to the present invention may advantageously be presented in the form of varnish or spray.
- a mixture of acetone and isopropyl alcohol was prepared. Water was added to the organic mixture and then urea was dissolved in the solution. PEG and the antifungal agent (miconazole nitrate) were added and dissolved in the solution. When the antifungal agent was completely dissolved, the humectant was added to the solution. Thereafter the polymer was added to the solution. The solution was brought to the final weight using the organic mixture prepared in the first step. All the steps of the varnish preparation were performed while continuously stirring the solution.
- films were cast from the varnish solutions onto glass surfaces (petri dishes). The solvent was allowed to evaporate for 24 h and the film was removed from the surface. Films of 100 ⁇ 104 cm in thickness were prepared and used for testing of (1) water residue in the film (2) dissolution rate of the active agents from the film and (3) sustained antifungal activity in vitro.
- Films were cut to a circular form, 2.54 cm 2 in area, and were weighed accurately. Film thickness was measured with a micrometer.
- the membranes were attached to a specially designed dissolution basket in which only one surface of the membrane was exposed to the dissolution medium. 150 ml of 1% sodium lauryl sulfate solution served as the dissolution medium. The dissolution rates were measured in a Van-Kel (VK 7000) dissolution test apparatus at 32° C. and 100 rpm rotating speed.
- VK 7000 Van-Kel
- a strain of Saccharomyces cerevisiea was used in this study.
- a 1:10 dilution of a stock suspension of the above organism was mixed with mycological culture medium and poured into petri dishes.
- 5 mm diameter discs of the film (Formulation No 1, 6, 7, 14) containing clotrimazole or miconazole nitrate were placed on the hardened medium and incubated for 24 h at 30° C. Thereafter the films were transferred to another set of petri dishes containing the same medium plus Saccharomyces cerevisiea.
- the measurements of the inhibition zone were discontinued after 6 days. There was no inhibition of Saccharomyces growth in control samples of the film containing no antifungal agent. The results reveal that the antifungal agent embedded in the film is pharmacologically active and is able to inhibit the growth of Saccharomyces cerevisiea strain for a prolonged period of time.
- compositions of the present invention may be applied to the infected nail and surrounding tissues once a day up to once a week.
- concentrations and duration of treatment is a function of the tissue being treated. It is to be noted that concentrations may also vary with the age and condition of the individual treated. It is to be further understood that for any particular subject, the frequency of application should be adjusted over time according to the individual need and professional judgment of the physician or person administering or supervising the administration of the formulations.
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Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/534,960 US7074392B1 (en) | 2000-03-27 | 2000-03-27 | Controllled delivery system of antifungal and keratolytic agents for local treatment of fungal infections |
AU28138/01A AU2813801A (en) | 2000-03-27 | 2001-03-21 | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
CA002341814A CA2341814C (fr) | 2000-03-27 | 2001-03-22 | Dispositif d'administration d'agents antifongiques et keratolytiques pour le traitement local d'infections fongiques de l'ongle et des tissus avoisinants |
EP01650031A EP1138314A3 (fr) | 2000-03-27 | 2001-03-26 | Système de libération controlée d'agents antimycotiques et kératolitiques pour le traitement local des infections fongiques des ongles et des tissus voisins |
ZA200102441A ZA200102441B (en) | 2000-03-27 | 2001-03-26 | Cntrolled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues. |
MXPA01003182A MXPA01003182A (es) | 2000-03-27 | 2001-03-27 | Sistema de liberacion controlada de agentes antifungicos y queratoliticos para el tratamiento local de las infecciones fungicas de la una y los tejidos circundantes. |
JP2001091489A JP2001316247A (ja) | 2000-03-27 | 2001-03-27 | 爪および周囲組織の真菌感染局所治療のための抗真菌性と角質溶解性薬剤の制御送達システム |
CN01119020A CN1324607A (zh) | 2000-03-27 | 2001-03-27 | 用于指甲和周围组织真菌感染局部治疗的抗真菌剂和溶角蛋白剂的可控释放系统 |
HK02103829.9A HK1041833A1 (zh) | 2000-03-27 | 2002-05-22 | 用於指甲和周圍組織真菌感染局部治療的抗真菌劑和溶角蛋白劑的可控釋放系統 |
US11/313,186 US7678366B2 (en) | 2000-03-27 | 2005-12-20 | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
US12/652,331 US8257688B2 (en) | 2000-03-27 | 2010-01-05 | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/534,960 US7074392B1 (en) | 2000-03-27 | 2000-03-27 | Controllled delivery system of antifungal and keratolytic agents for local treatment of fungal infections |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US11/313,186 Continuation US7678366B2 (en) | 2000-03-27 | 2005-12-20 | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
Publications (1)
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US7074392B1 true US7074392B1 (en) | 2006-07-11 |
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ID=24132231
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US09/534,960 Expired - Fee Related US7074392B1 (en) | 2000-03-27 | 2000-03-27 | Controllled delivery system of antifungal and keratolytic agents for local treatment of fungal infections |
US11/313,186 Expired - Fee Related US7678366B2 (en) | 2000-03-27 | 2005-12-20 | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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US11/313,186 Expired - Fee Related US7678366B2 (en) | 2000-03-27 | 2005-12-20 | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
Country Status (9)
Country | Link |
---|---|
US (2) | US7074392B1 (fr) |
EP (1) | EP1138314A3 (fr) |
JP (1) | JP2001316247A (fr) |
CN (1) | CN1324607A (fr) |
AU (1) | AU2813801A (fr) |
CA (1) | CA2341814C (fr) |
HK (1) | HK1041833A1 (fr) |
MX (1) | MXPA01003182A (fr) |
ZA (1) | ZA200102441B (fr) |
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- 2001-03-26 EP EP01650031A patent/EP1138314A3/fr not_active Withdrawn
- 2001-03-26 ZA ZA200102441A patent/ZA200102441B/xx unknown
- 2001-03-27 JP JP2001091489A patent/JP2001316247A/ja not_active Abandoned
- 2001-03-27 CN CN01119020A patent/CN1324607A/zh active Pending
- 2001-03-27 MX MXPA01003182A patent/MXPA01003182A/es unknown
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- 2002-05-22 HK HK02103829.9A patent/HK1041833A1/zh unknown
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US7678366B2 (en) * | 2000-03-27 | 2010-03-16 | Taro Pharmaceutical Industries Limited | Controlled delivery system of antifungal and keratolytic agents for local treatment of fungal infections of the nail and surrounding tissues |
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US10543276B2 (en) | 2016-08-08 | 2020-01-28 | Marlinz Pharma, LLC | Topical compositions |
WO2018102195A1 (fr) * | 2016-12-02 | 2018-06-07 | Revlon Consumer Products Corporation | Composition pour enlever le vernis à ongles |
US12029812B2 (en) | 2022-09-19 | 2024-07-09 | Cmpd Licensing, Llc | Compositions and methods for treating an infection |
Also Published As
Publication number | Publication date |
---|---|
EP1138314A2 (fr) | 2001-10-04 |
US20060120977A1 (en) | 2006-06-08 |
HK1041833A1 (zh) | 2002-07-26 |
JP2001316247A (ja) | 2001-11-13 |
CA2341814C (fr) | 2008-06-10 |
AU2813801A (en) | 2001-10-04 |
US7678366B2 (en) | 2010-03-16 |
ZA200102441B (en) | 2001-09-28 |
MXPA01003182A (es) | 2004-05-31 |
CA2341814A1 (fr) | 2001-09-27 |
CN1324607A (zh) | 2001-12-05 |
EP1138314A3 (fr) | 2004-01-02 |
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